Global Analysis of TDP-43 Interacting Proteins Reveals Strong Association with RNA Splicing and Translation Machinery

被引:388
作者
Freibaum, Brian D. [1 ]
Chitta, Raghu K. [2 ]
High, Anthony A. [2 ]
Taylor, J. Paul [1 ]
机构
[1] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA
关键词
TDP-43; RNA granule; stress granule; ALS; FTLD; hnRNP; RNA metabolism; RNA splicing; RNA translation; AMYOTROPHIC-LATERAL-SCLEROSIS; BINDING-PROTEIN; MASS-SPECTROMETRY; STATISTICAL-MODEL; GENE-EXPRESSION; STRESS GRANULES; MUTATIONS; IDENTIFICATION; DISEASE; REGULATOR;
D O I
10.1021/pr901076y
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
TDP-43 is a highly conserved and ubiquitously expressed member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins. Recently, TDP-43 was shown to be a major disease protein in the ubiquitinated inclusions characteristic of most cases of amyotrophic lateral sclerosis (ALS), tau-negative frontotemporal lobar degeneration (FTLD), and inclusion body myopathy. In these diseases, TDP-43 is redistributed from its predominantly nuclear location to ubiquitin-positive, cytoplasmic foci. The extent to which TDP-43 drives pathophysiology is unknown, but the identification of mutations in TDP-43 in familial forms of ALS and FTLD-U suggests an important role for this protein in pathogenesis. Little is known about TDP-43 function and only a few TDP-43 interacting proteins have been previously identified, which makes further insight into both the normal and pathological functions of TDP-43 difficult. Here we show, via a global proteomic approach, that TDP-43 has extensive interaction with proteins that regulate RNA metabolism. Some interactions with TDP-43 were found to be dependent on RNA-binding, whereas other interactions are RNA-independent. Disease-causing mutations in TDP-43 (A315T and M337V) do not alter its interaction profile. TDP-43 interacting proteins largely cluster into two distinct interaction networks, a nuclear/splicing cluster and a cytoplasmic/translation cluster, strongly suggesting that TDP-43 has multiple roles in RNA metabolism and functions in both the nucleus and the cytoplasm. Finally, we found numerous TDP-43 interactors that are known components of stress granules, and indeed, we find that TDP-43 is also recruited to stress granules.
引用
收藏
页码:1104 / 1120
页数:17
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